: The long-term objective of this project is to understand how tumors evade recognition and rejection by cells of the immune system. Optimal therapeutic strategies require the development of drugs that strengthen or inhibit specific immune responses, providing useful treatments for human cancer, organ transplantation and autoimmune diseases. In keeping with this goal, the investigator's laboratory is studying the molecular mechanisms governing the regulation of T lymphocytes. Most immune responses involve the physiological activation of resting T cells into responsive effector or regulatory cells. This process begins with the direct interactions between T cells and APCs. At least two signals are needed for antigen-specific T cell activation. The first signal occurs when the antigen-specific TCR-CD3 complex binds to antigen peptides attached to MHC molecules. Ligation of TCR-CD3 alone, in the absence of a second, "costimulatory" signal, can actually prevent the initiation of an immune response, causing mature T cells to become unresponsive or anergic. The costimulatory signal occurs when the CD28 receptor on T cells binds to one of its ligands (CD80 or CD86) on the surface of APCs. Intriguingly, CD80 and CD86 differ in their capacity to promote the differentiation of T cells into functionally specialized sub-populations of Th1 and Th2 cells. As an added layer of complexity, a negative immunoregulatory signal is sent when CD80 or CD86 binds CD152, a CD28-related receptor on T cell surfaces. Thus, CD28 family signaling provides an excellent model system for studying: (1) whether a single receptor can transmit distinct ligand-specific signals and 2) how coordinate regulation by multiple receptors can determine the outcome of cellular responses. These two broad issues are the focus of this application, and will be addressed in three specific Aims: Specific Aim 1 is to analyze ligand-specific changes in the CD28 signaling complex; Specific Aim 2 is to investigate whether there are lateral interactions between the TCR-CD3, CD28 and CTLA-4 signaling complexes; and Specific Aim 3 is to identify and modulate early regulators of co-stimulation. These studies will contribute to our understanding of the molecular mechanisms involved in co-stimulation through the CD28 receptor.